Paget's disease of bone, or osteitis deformans, is a bone disorder characterized by rapid bone remodeling, resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3-4% of subjects over the age of 40. The causes of Paget's disease are unknown but, recently, two lines of evidence have converged to suggest that Paget's disease may have a genetic component to its predisposition. First, linkage analysis of families with multigenerational Paget's disease show linkage to a region of chromosome 18q near to the polymorphic locus D18S42. This subregion has also been identified as the location for the locus for Familial Expansile Osteolysis (FEO), a hereditary disease similar to Paget's disease. Secondly, one of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1-5% of Paget's patients develop osteosarcoma, which represents an increase of risk that is several thousand-fold over the general population, and is the underlying basis for a significant fraction of osteosarcoma after 40 years of age. Tumor-specific loss of constitutional heterozygosity (LoH) analysis of osteosarcomas by the applicant laboratory has identified a putative tumor suppressor gene that maps to the same subregion of chromosome 18q that was linked to both familial Paget's and FEO. This association between Paget's disease and osteosarcoma suggests either a common genetic pathway, or two closely associated genes. The underlying hypothesis of this IRPG is that the association between osteosarcoma tumorigenesis, familial Paget's disease and FEO is due to the presence of either a gene, or several closely associated genes in this region of chromosome 18q. To test this hypothesis, candidate genes will be isolated from within the region defined by both the familial Paget's disease families and the minimal region of LoH in osteosarcomas, and these candidate genes will be tested for evidence that one or more of them is responsible for predisposition to Paget's disease and/or osteosarcoma.